RU2810755C2 - Powder containing buffer salt and amino acid, dissolution of such powder to nutrient product and methods of use of such nutrient product - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a composition in the form of a powder for preparing a nutritious product. The powder for obtaining a nutritional product contains a phosphate salt, at least one glycine or a functional derivative thereof, at least one N-acetylcysteine, L-cysteine or a functional derivative thereof, vitamin E, vitamin C, vitamin B₂ and zinc. Moreover, the powder has at least one characteristic selected from the group consisting of the following: (i) amino acids are present in the powder in an amount at least partially including an amino acid in a form selected from the group consisting of free form, dipeptides, tripeptides and their mixtures, and (ii) the powder is substantially free of enzymes and antibodies. The liquid nutritional product contains the above powder and an ingredient selected from the group consisting of an acid component, protein and mixtures thereof. A method of reducing or preventing protein denaturation and protein coagulation caused by dissolving a powder in a liquid containing an ingredient selected from the group consisting of a protein or a mixture of a protein and an acid component includes a step selected from the group consisting of (i) dry mixing a phosphate salt with an amino acid and (ii) drying an aqueous solution containing a phosphate salt and an amino acid, wherein the powder contains a phosphate salt, at least one glycine or a functional derivative thereof, at least one N-acetylcysteine, L-cysteine or a functional derivative thereof, vitamin E, vitamin C, vitamin B₂ and zinc, and has at least one characteristic selected from the group consisting of the following: (i) amino acids are present in the powder in an amount at least partially comprising the amino acid in a form selected from the group, consisting of free form, dipeptides, tripeptides and mixtures thereof, and (ii) the powder is substantially free of enzymes and antibodies.

EFFECT: invention makes it possible to minimize or prevent protein denaturation and protein coagulation when dissolving the powder in a liquid.

24 cl, 4 dwg, 1 ex

Description

Prerequisites for creating the invention

The present description essentially relates to compositions and methods that use a buffer salt, an amino acid, and optionally a vitamin and/or mineral. In a non-limiting embodiment, the composition is a powder that contains at least one glycine or a functional derivative thereof, at least one N-acetylcysteine, L-cysteine or a functional derivative thereof, and a buffer salt; and the powder can be dissolved in liquid to form a nutritional product.

Population aging is a noticeable demographic phenomenon. As the growth of the elderly population has exceeded the overall population growth due to increasing life expectancy, the proportion of elderly people relative to the rest of the population has increased significantly. For example, in 1950, one in twelve people was at least 60 years old, and by the end of 2000, one in ten were aged 60 or older. By the end of 2050, one in five people in the world is projected to be 60 years of age or older.

Elderly or aging individuals often suffer from some degree of cognitive impairment, including cognitive decline that progresses with age, and age-related changes in brain morphology and cerebrovascular function are common. With age, there is a consistent decline in cognitive abilities across a range of cognitive functions, including processing speed, attention, episodic memory, spatial awareness, and goal-directed activity. Brain imaging studies have shown that these normal age-related cognitive declines are associated with a decrease in the volume of both gray and white matter in the brain, with the frontostriatal system most often affected by aging. This decrease in cortical volume can be explained by a number of destructive cellular processes associated with normal aging, such as the accumulation of free radical damage over time leading to oxidative damage, chronic low-grade inflammation, accumulation of homocysteine (increased levels of which are a risk factor for cognitive decline and dementia) and decreased mitochondrial efficiency. Along with direct cellular damage, the brain is also indirectly damaged due to effects on microvascular structures.

It is obvious that the pathology of aging, as well as dementia, is a complex of these interrelated, interacting factors. For example, mitochondrial dysfunction leads to increased oxidative stress, and oxidative stress can cause inflammation and vascular damage.

Additionally, cognitive decline is an early prognostic factor or pathology of Alzheimer's disease, and it begins before the onset of dementia. In this context, a comprehensive cognitive assessment provides a reliable means of assessing cognitive decline that precedes dementia. Reliable evidence suggests that maintaining brain health and preventing cognitive decline with age can prevent or slow the progression of dementia caused by Alzheimer's disease and other age-related neuropathologies.

In biology and psychology, the term "stress" refers to the consequences of a human or other animal's failure to respond appropriately to physiological, emotional, or physical threats, whether actual or imagined. The psychobiological features of stress can manifest as signs of oxidative stress, that is, an imbalance between the production and expression of reactive oxygen species and the ability of the biological system to quickly eliminate the toxic effects of reactive intermediates or repair the resulting damage. Disturbances in the normal redox status of tissues can lead to toxic effects through the production of peroxides and free radicals that damage all cellular components, including proteins, lipids, and DNA. Some active oxidizing agents can even act as messengers through a phenomenon called “redox signaling.”

In humans, oxidative stress is involved in many diseases. Examples include atherosclerosis, Parkinson's disease, heart failure, myocardial infarction, Alzheimer's disease, schizophrenia, bipolar disorder, fragile X syndrome, and chronic fatigue syndrome.

One source of active oxygen under normal conditions in humans is the leakage of activated oxygen from mitochondria through oxidative phosphorylation. Other enzymes capable of producing superoxide (O2-) are xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidases), and cytochrome P450s. Hydrogen peroxide, another strong oxidizing agent, is generated by a wide range of enzymes, including several oxidases. Reactive oxygen species play an important role in cellular signaling called redox signaling. Thus, to maintain proper cellular homeostasis, it is necessary to maintain a balance between the production and consumption of active oxygen.

Oxidative stress contributes to tissue damage after irradiation and hyperoxia. It is also thought to play an important role in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease.

Oxidative stress is also thought to be associated with certain cardiovascular diseases because oxidation of low-density lipoprotein (LDL) in the vascular endothelium is a precursor to plaque formation. Oxidative stress also plays a role in the ischemic cascade due to oxygen reperfusion injury following hypoxia. This cascade includes both strokes and heart attacks. Oxidative stress also contributes to chronic fatigue syndrome.

Moreover, the free radical theory of aging suggests that the biological process of aging leads to increased oxidative stress in older adults. The ability of cells to resist the damaging potential of oxidative stress is determined by the vital balance between the production of oxidative free radicals and the range of protective antioxidants available to the cell. There are many antioxidant defense systems, and glutathione (GSH) is the most abundant intracellular component of all antioxidant defenses. GSH, a tripeptide, is synthesized from the precursor amino acids glutamate, cysteine, and glycine in two steps catalyzed by glutamate cysteine ligase (GCL, also known as gamma-glutamylcysteine synthetase, EC 6.3.2.2) and gamma-L-glutamyl-L-cysteine: glycyligase (also known as glutathione synthetase, EC 6.3.2.3), and GSH synthesis occurs de novo in cells.

Summary of the invention

Acidic amino acids such as N-acetylcysteine (NAC) can denature proteins in liquids. Current solutions use alkaline additives such as potassium hydroxide and sodium hydroxide to raise the pH of protein-containing liquids. However, the present inventors have observed that increasing the pH of a protein-containing solution can change the configuration of protein structures, which may result in denaturation or gelation prior to the addition of acidic amino acids.

The present inventors have surprisingly discovered that buffer salts such as disodium phosphate and/or dibasic potassium phosphate can be mixed with acidic amino acids and then added to liquids containing protein such as milk protein, vegetable protein, collagen or mixtures thereof. Thus, protein denaturation can be avoided at various concentrations and conditions by establishing and/or maintaining a stable pH level of the liquid.

Indeed, proteins are sensitive to changes in pH in a liquid environment, and even small changes in pH can cause disruption of the protein structure and denaturation, which can lead to gelation, precipitation and aggregation. One way to change the pH of the environment is by adding acidic or alkaline components. For example, amino acids have a chemical structure that can cause pH to increase or decrease. Therefore, addition of these amino acids to protein-containing liquid products may result in denaturation due to an increase or decrease in pH. As set forth herein below, the present inventors have evaluated the addition of buffer salts to prevent sudden changes in the pH of a protein-containing liquid. The present inventors found that these buffer salts minimized pH changes and reduced protein precipitation compared to cases where no buffer salts were used.

Accordingly, in a general embodiment, provided herein is a powder containing a buffer salt and an amino acid. The powder has at least one characteristic selected from the group consisting of the following: (i) the amino acid is present in an amount at least partially comprising the amino acid in a form selected from the group consisting of free form, dipeptides, tripeptides and mixtures thereof, and (ii) the powder is essentially free of enzymes and antibodies.

In one embodiment, the amino acid comprises an acidic amino acid.

In one embodiment, the powder further contains at least one of a vitamin or mineral.

In one embodiment, the powder further contains at least one of calcium, sodium or potassium.

In one embodiment, the amino acid contains L-cysteine, glycine and L-glutamate, which are provided with glutathione in the powder.

In one embodiment, the amino acid contains at least one N-acetylcysteine or a functional derivative thereof.

In one embodiment, the amino acid contains a combination of at least one N-acetylcysteine or a functional derivative thereof and at least one glycine or a functional derivative thereof.

The powder may be in a unit dosage form containing a combination of at least one N-acetylcysteine, L-cysteine, or a functional derivative thereof, and at least one glycine or a functional derivative thereof, in an amount effective to treat, reduce the incidence of, or reduce the severity of at least at least one condition selected from the group consisting of metabolic syndrome, age-related metabolic decline, and muscle performance.

The powder may be in a unit dosage form containing a combination of at least one N-acetylcysteine, L-cysteine or a functional derivative thereof and at least one glycine or a functional derivative thereof in an amount effective for at least one of (i) treatment or preventing at least one physical condition selected from the group consisting of oxidative stress, a condition associated with oxidative stress (e.g., aging and its consequences, e.g., skin aging), decreased glutathione levels, a condition associated with decreased glutathione levels, or ( ii) improving one or more of fetal metabolic programming to prevent the subsequent development of obesity, prediabetes and/or diabetes, maternal and fetal health in gestational diabetes, exercise capacity and physical function, quality of life, life expectancy, memory, cognitive function, post-traumatic recovery and survival or recovery from injury and surgery.

The powder may be in a unit dosage form containing a combination of at least one N-acetylcysteine or a functional derivative thereof and at least one glycine or a functional derivative thereof in an amount effective to treat or prevent at least one physical condition selected from the group, consisting of the harmful effects of aging, muscle wasting, prediabetes, gestational diabetes, type I diabetes, type II diabetes, complications of diabetes, insulin resistance, metabolic syndrome, dyslipidemia, overweight, obesity, increased cholesterol levels, increased triglyceride levels, increased fatty levels acids, fatty liver disease, kidney disease, cardiovascular disease, neurodegenerative disease, cognitive impairment, myopathy such as statin-induced myopathy, non-alcoholic steatohepatitis, tinnitus, dizziness, hangover syndrome, hearing impairment, osteoporosis, hypertension, atherosclerosis / coronary artery disease, myocardial damage after stress, traumatic brain injury, cystic fibrosis, inflammation, cancer and HIV infection.

In one embodiment, the powder is substantially free of proteins having at least four amino acid residues.

In another embodiment, the present invention provides a method of reducing or preventing protein denaturation and/or protein coagulation by dissolving the powder in a liquid containing an ingredient selected from the group consisting of a protein, an acid component, and a mixture thereof. The method includes a step selected from the group consisting of (i) dry mixing a buffer salt with an amino acid and (ii) drying an aqueous solution containing a buffer salt and an amino acid. The powder has at least one characteristic selected from the group consisting of the following: (i) the amino acid is present in an amount at least partially comprising the amino acid in a form selected from the group consisting of free form, dipeptides, tripeptides and mixtures thereof, and (ii) the powder is essentially free of enzymes and antibodies.

In one embodiment, the amino acid contains at least one N-acetylcysteine or a functional derivative thereof.

In an embodiment, the amino acid contains a combination of at least one N-acetylcysteine, L-cysteine, or a functional derivative thereof, and at least one glycine or a functional derivative thereof.

In one embodiment, the powder further contains at least one of a vitamin or mineral.

In another embodiment, provided herein is a liquid nutritional product comprising a buffer salt, an amino acid, and an ingredient selected from the group consisting of an acid component, a protein, and mixtures thereof. The nutritional product is prepared by a process comprising dissolving a powder containing a buffer salt and an amino acid in a liquid containing the ingredient. The powder has at least one characteristic selected from the group consisting of the following: (i) the amino acid is present in an amount at least partially comprising the amino acid in a form selected from the group consisting of free form, dipeptides, tripeptides and mixtures thereof, and (ii) the powder is essentially free of enzymes and antibodies.

In one embodiment, the nutritional product is a beverage.

In one embodiment, the liquid contains an acid component that is at least one of a juice or a polyphenol (eg, a flavonoid).

In one embodiment, the liquid contains a protein selected from the group consisting of milk protein, vegetable protein, collagen, and mixtures thereof.

In another embodiment, provided herein is a method of producing a powder prepared for dissolution in a liquid to form a nutritional product. The liquid contains an ingredient selected from the group consisting of a protein, an acid component, and a mixture thereof. The method includes a step selected from the group consisting of (i) dry mixing a buffer salt with an amino acid and (ii) drying an aqueous solution containing a buffer salt and an amino acid. The powder has at least one characteristic selected from the group consisting of the following: (i) the amino acid is present in an amount at least partially comprising the amino acid in a form selected from the group consisting of free form, dipeptides, tripeptides and mixtures thereof, and (ii) the powder is essentially free of enzymes and antibodies.

In one embodiment, the amino acid contains at least one N-acetylcysteine, L-cysteine, or a functional derivative thereof.

In an embodiment, the amino acid contains a combination of at least one N-acetylcysteine, L-cysteine, or a functional derivative thereof, and at least one glycine or a functional derivative thereof.

In one embodiment, the powder further contains at least one of a vitamin or mineral.

An advantage of one or more embodiments presented herein is to facilitate the dissolution of an amino acid such as N-acetylcysteine, L-cysteine and/or glycine by minimizing or preventing denaturation and coagulation of the protein in the liquid in which the amino acid such as is dissolved as a liquid containing an acidic component, which is at least one of a juice or a polyphenol (eg, a flavonoid), and/or containing a protein, such as milk protein, vegetable protein, collagen, or mixtures thereof.

Another advantage of one or more embodiments of the present invention is to facilitate the dissolution of a powder containing a vitamin and/or mineral that may increase precipitation, such as sodium, potassium or calcium, by minimizing or preventing the adverse effects of such compounds on dissolving powder in liquid.

Another benefit of one or more embodiments presented herein is the restoration of glutathione pools that are depleted with age.

One or more embodiments presented herein have the advantage of helping to reverse the metabolic slowdown associated with aging.

Another benefit of one or more embodiments presented herein is to promote increased fatty acid metabolism.

One or more embodiments presented herein have the advantage of helping to maintain healthy levels of LDL cholesterol and fatty acids in the blood.

Another benefit of one or more embodiments presented herein is the replenishment of essential amino acids, sufficient quantities of which become less available to cells during the aging process.

Another benefit of one or more embodiments presented herein is the provision of amino acids that are precursors to glutathione production, which is important for cell function and cell protection.

One or more embodiments presented herein have the advantage of helping to increase cellular glutathione levels.

Another advantage of one or more embodiments of the present invention is to increase glutathione concentrations, which fall with age.

Another benefit of one or more embodiments presented herein is to help maintain healthy muscle mass.

One or more embodiments presented herein have the advantage of helping to reduce oxidative stress in the body.

Another benefit of one or more embodiments provided herein is the support of the normal immune system by modulating glutathione levels.

Additional features and benefits are described herein and will be apparent upon viewing the following figures and reading the detailed description.

Brief description of graphic materials

In fig. 1 shows an experimental test of the dissolution of powdered N-acetylcysteine (NAC) without buffer salts in a milk-based liquid at room temperature, as described herein.

In fig. 2 shows an experimental test of the dissolution of powdered NAC with buffered salts in a milk-based liquid at room temperature as described herein.

In fig. 3 shows an experimental test of the dissolution of powdered NAC and glycine without buffer salts in a milk-based liquid at room temperature as described herein.

In fig. 4 shows an experimental test of the dissolution of powdered NAC and glycine with buffered salts in a milk-based liquid at room temperature as described herein.

Detailed description

Definitions

Below are some definitions. However, definitions may appear below in the “Embodiments” section, and the above heading “Definitions” does not mean that the above descriptions in the “Embodiments” section are not definitions.

Unless otherwise indicated, all percentages herein are expressed by weight of the total weight of the composition. As used herein, the terms “about”, “approximately” and “substantially” refer to numbers in a numerical range, for example, in the range of -10% to +10% of said number, preferably in the range of -5% to +5% of said number, more preferably -1% to +1% of said number, and most preferably -0.1% to +0.1% of said number. It should be understood that all numeric ranges herein include all integers and fractions included in the range. Moreover, these numerical ranges should be considered to support the claim referring to any number or subset of numbers within that range. For example, the description "from 1 to 10" should be considered to include the range "from 1 to 8", "from 3 to 7", "from 1 to 9", "from 3.6 to 4.6", "from 3, 5 to 9.9", etc.

As used in this specification and the accompanying claims, the singular forms include plural references unless the context clearly requires otherwise. Thus, for example, the reference to “one component” or “this component” implies the presence of two or more components.

The words “contain,” “contains,” and “comprising” should be interpreted as inclusive and not exclusive. Likewise, the terms “include,” “including,” and “or” should be interpreted in an inclusive sense unless such interpretation is clearly inconsistent with the context. However, the compositions described herein may not contain any element not specifically described herein. Thus, a description of an embodiment using the term “comprising” includes a description of embodiments “consisting essentially of” and “consisting of” the specified components. A composition "consisting essentially of" contains at least 50% by weight of said components, preferably at least 75% by weight of said components, more preferably at least 85% by weight of said components, most preferably at least 95 wt.% of these components.

The term "and/or" used in the context of "X and/or Y" should be interpreted as "X" or "Y" or "X and Y". Likewise, “at least one of X or Y” should be interpreted as “X” or “Y” or “X and Y”. For example, “at least one glycine or a functional derivative thereof” should be interpreted as “glycine” or “a functional derivative of glycine” or “both glycine and a functional derivative of glycine.”

As used herein, the terms “for example” and “such as,” particularly when followed by a listing of terms, are used for exemplary and illustrative purposes only and should not be considered exclusive or exhaustive. As used herein, a condition “associated with” or “caused by” another condition means that the conditions occur simultaneously, preferably means that the conditions are caused by the same underlying condition, and most preferably means that one of the specified conditions is caused by another the specified condition.

The term “nutritional product” as used herein means a composition that is intended for ingestion by an individual, such as a human, and provides that individual with at least one nutrient. The nutritional products of the present invention, including many embodiments described herein, may contain, consist of or consist essentially of the elements described herein, as well as any additional or optional ingredients, components or elements described herein or otherwise suitable for use in the diet.

As used herein, the term “isolated” means separated from one or more other compounds or components with which the compound may otherwise be found, for example, found in nature. For example, “isolated” preferably means that the compound is separated from at least a portion of the cellular material with which it is typically found in nature. In one embodiment, the isolated compound is pure, i.e. does not contain any other compound.

“Prevention” includes reducing the risk and/or severity of a condition or disorder. The terms “treat” and “treat” include both prophylactic or preemptive treatment (which prevents and/or slows the progression of the target condition or disorder) and curative, therapeutic or disease-modifying treatment, including therapeutic measures that cure, slow, reduce symptoms and/or stop the progression of a diagnosed condition or disorder; and treating patients at risk of contracting a disease or suspected of contracting a disease, as well as patients who have or have been identified as suffering from a disease or medical condition. The terms “treat” and “treat” do not necessarily imply that the subject receives treatment until complete recovery. The terms “treating” and “treating” also refer to maintaining and/or promoting health in an individual who does not suffer from a disease, but who may be susceptible to developing a disease condition. The terms “treating” and “treating” should also include potentiation or other enhancement of one or more primary preventive or therapeutic measures. By way of non-limiting examples, treatment may be performed by a patient, caregiver, physician, nurse, or other health care professional.

As used herein, the term “unit dosage form” refers to physically discrete units suitable for use as unitary dosages for human and animal subjects, each unit containing a predetermined amount of a composition described herein in an amount sufficient to achieve the desired effect , preferably in combination with a pharmaceutically acceptable diluent, carrier or carrier medium. Specifications for a unit dosage form depend on the specific compounds used, the effect achieved, and the pharmacodynamics of each compound in the host. In one embodiment, the unit dosage form may be a predetermined amount of powder in a sachet.

The "subject" or "individual" is a mammal, preferably a human. The term "elderly" in the context of a person means at least 60 years of age from birth, preferably over 63 years of age, more preferably over 65 years of age, and most preferably over 70 years of age. The term "older adult" in a human context means at least 45 years of age from birth, preferably greater than 50 years, more preferably greater than 55 years, and includes older individuals.

As used herein, the term “effective amount” means an amount that effectively prevents a deficiency, treats a disease or medical condition in an individual, or more generally reduces symptoms, controls the progression of a disease, or provides a nutritional, physiological, or medical benefit to an individual. Relative terms “improved”, “increased”, “strengthened”, etc. refer to the effects of a composition described herein, namely a composition containing at least one glycine or a functional derivative thereof, at least one N-acetylcysteine, L-cysteine or a functional derivative thereof, and a buffer salt, as compared to a composition not containing one or more of these compounds, but otherwise identical. As used herein, the term “stimulation” refers to increasing or inducing a specific level relative to the level prior to administration of the composition described herein.

The term sarcopenia is defined as age-related loss of muscle mass and muscle functionality (including muscle strength and walking speed). As used herein, frailty is defined as a clinically recognizable state of increased vulnerability resulting from aging-related decline in the reserves and functions of multiple physiological systems, resulting in an impaired ability to cope with daily or acute stressors. In the absence of an established quantitative standard, frailty is functionally defined by Fried et al. as meeting three of five phenotypic criteria indicating energy impairment: (1) weakness (grip strength initially in the bottom 20% of the population, adjusted for sex and body mass index), (2) poor endurance and energy reserve (self-reported VO ₂ max-related wasting), (3) slowness (baseline in bottom 20% of population based on time required to walk 15 feet adjusted for sex and standing height), (4) low physical activity (weighted an estimate of kilocalories burned per week at baseline, the lowest physical activity quintile identified for each sex; for example, less than 383 kcal/week for men and less than 270 kcal/week for women), and/or unintentional weight loss (10 pounds in the past year ). Fried LP, Tangen CM, Walston J, et al., “Frailty in older adults: evidence for a phenotype.” J. Gerontol. A. Biol. Sci. Med. Sci. 56(3):M146–M156 (2001). A pre-frailty stage in which one or two of these criteria is present identifies a high risk of progression to frailty.

“Cachexia” is a severe condition of body wasting characterized by severe weight loss, anorexia, asthenia and anemia. Cachexia is a common feature of a number of diseases, such as cancer, sepsis, congestive heart failure, rheumatoid arthritis, and acquired immunodeficiency syndrome (AIDS).

A person is defined as “overweight” if their body mass index (BMI) is between 25 and 30 kg/ ^m2 . “Obesity” in a person is defined as a BMI of at least 30 kg/m ² , for example, 30–39.9 kg/m ² . “Weight loss” is a decrease in total body weight. Weight loss may, for example, refer to the loss of total body weight for the purpose of improving one or more of health, fitness or appearance.

The term diabetes covers both type I and type II forms of the disease. Non-limiting examples of risk factors for diabetes include: waist circumference greater than 40 inches in men or 35 inches in women, blood pressure 130/85 mmHg. Art. or higher, triglycerides more than 150 mg/dL, fasting blood glucose more than 100 mg/dL, or high-density lipoprotein less than 40 mg/dL in men or 50 mg/dL in women.

As used herein, the term “metabolic syndrome” refers to a combination of medical disorders that, when co-occurring, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States, and the prevalence increases with age. Some studies have found the prevalence in the United States to be 25% of the population. According to the international consensus definition of the International Diabetes Foundation (2006), metabolic syndrome is the central type of obesity plus any two of the following factors.

Elevated triglycerides: > 150 mg/dL (1.7 mmol/L) or specific treatment for such lipid abnormality;

reduced HDL cholesterol: <40 mg/dL (1.03 mmol/L) in men, <50 mg/dL (1.29 mmol/L) in women, or specific treatment for this lipid abnormality;

high blood pressure: systolic blood pressure > 130 or diastolic blood pressure > 85 mm Hg. Art. or treatment of previously diagnosed hypertension; And

elevated fasting plasma glucose (FPG) > 100 mg/dL (5.6 mmol/L) or previously diagnosed type 2 diabetes.

As used herein, the term “neurodegenerative disease” or “neurodegenerative disorder” refers to any condition associated with the progressive loss of functional neurons in the central nervous system. In one embodiment, the neurodegenerative disease is associated with age-related cell death. Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (also known as ALS and Lou Gehrig's disease), AIDS dementia complex, adrenoleukodystrophy, Alexander disease, Alper disease, ataxia telangiectasia, Batten disease , bovine spongiform encephalopathy (BSE), Canavan disease, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia with Lewy bodies, fatal familial insomnia, frontotemporal lobar degeneration, Kennedy disease, Krabbe disease, Lyme disease, Machado-Joseph disease, multiple sclerosis, multiple system atrophy, neuroacanthocytosis, Niemann-Pick disease, Pick's disease, primary lateral sclerosis, progressive supranuclear gaze palsy, Refsum's disease, Sandhoff's disease, diffuse myelinoclastic sclerosis, spinocerebellar ataxia, subacute combined degeneration of the spinal cord, tabes dorsalis, disease Tay-Sachs, toxic encephalopathy, transmissible spongiform encephalopathy and staggering hedgehog syndrome.

As used herein, the term “cognitive performance” refers to how well a subject performs one or more cognitive functions. As used herein, the term “cognitive function” refers to any mental process by which an individual learns, perceives, or makes sense of ideas. It involves symbol manipulation, for example, all aspects of perception, thinking, reasoning and remembering, and includes, for example, perception, memory, attention, speech comprehension, speech generation, reading comprehension, image creation, learning and preferably logic. Typically it will relate to at least memory.

Methods for measuring cognitive function are well known and may include, for example, individual tests or groups of tests for any aspect of cognitive function. One such test is the Prado Test of Cognitive Function, developed by Margallo-Lana et al. (2003) J. Intelligence. Disability Res. 47:488-492. Another such test is the Mini-Mental State Examination (MMSE), which is designed to assess orientation in time and space, writing, attention and computation, memory, language use and comprehension, repetition and execution of complex commands. Folstein et al. (1975) J. Psych. Res. 12:189-198. Other tests that can be used to measure cognitive function include the Alzheimer's Disease Assessment Scale (ADAS-Cog) (Rosen et al. (1984) Am. J. Psychiatry. 141(11): 1356-64) and the Cambridge Automated Neuropsychological Battery tests (CANTAB) (Robbins et al. (1994) Dementia. 5(5):266-81). Such tests can be used to objectively assess cognitive function so that changes in cognitive function can be measured and compared, for example, in response to treatment in accordance with the methods described herein.

As used herein, the term “cognitive disorder” refers to any condition that impairs cognitive function. Non-limiting examples of cognitive impairment include delirium, dementia, learning disorder, attention deficit disorder (ADD), and attention deficit hyperactivity disorder (ADHD).

As used herein, the term “amino acid” includes standard (proteinogenic) amino acids, as well as derivatives of standard amino acids, such as compounds resulting from reaction with an amino group, carboxyl group or side chain functional group of an amino acid or the replacement of any hydrogen with a heteroatom. Non-limiting examples of suitable amino acid derivatives as used herein include amino acid esters such as methyl esters, amino acid tert-butyl esters, benzyl esters and ethyl esters. An “acidic” amino acid is any amino acid or derivative capable of donating a hydron (proton or hydrogen ion H+) or forming a covalent bond with a pair of electrons.

As used herein, the term “powder” means a composition in which any moisture constitutes no more than 6% by weight of the composition.

Embodiments

One aspect of the present disclosure is a powder prepared for dissolution in a liquid to form a nutritional product, the powder containing a buffer salt, an amino acid, and optionally at least one vitamin or mineral. In one embodiment, the amino acid contains one or both of (i) at least one glycine or a functional derivative thereof or (ii) at least one N-acetylcysteine, L-cysteine or a functional derivative thereof. In one embodiment, the amino acid contains L-cysteine, L-glutamic acid and glycine, which are provided with glutathione in the powder.

Non-limiting examples of suitable vitamins include vitamin C and B vitamins, and other non-limiting examples of suitable vitamins include ascorbic acid, ascorbyl palmitate, vitamins B1, B2, B6, B12 and niacin (B3) or a combination thereof. Vitamins may also include vitamins A, D, E and K and acid vitamins such as pantothenic acid, folic acid and biotin. Vitamin A may be present in the form of vitamin A palmitate and/or beta-carotene. Vitamin D3 is an example of a suitable form of vitamin D, and vitamin D2 may also be used in some embodiments.

Non-limiting examples of suitable minerals include calcium, sodium, magnesium, iron, zinc, iodine, copper, phosphorus, manganese, potassium, chromium, molybdenum, selenium, nickel, tin, silicon, vanadium and boron.

The powder can be administered in an amount that provides the recommended daily requirement (RDR) for the vitamin and/or mineral. In some embodiments, the unit dosage form of the powder contains a predetermined proportion of the RDI for the vitamin and/or mineral, for example, about 50% RDP, about 75% RDP, about 100% RDP, or intermediate values. For example, a single powder dosage form may contain about 50% of the RDI for a vitamin and/or mineral, such that administration of two unit dosage forms in one day provides approximately the entire RDI for the respective vitamin and/or mineral. In another example, a single powder dosage form may contain 100% of the RDI for a vitamin and/or mineral such that administration of one unit dosage form provides approximately the entire RDI for the corresponding vitamin and/or mineral.

The preferred vitamin and mineral blend contains vitamin E, vitamin C, vitamin B2 and zinc. Thus, a preferred embodiment of the powder contains a buffer salt, at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof, vitamin E, vitamin C, vitamin B2 and zinc, most preferably vitamins and minerals , introduced in an amount within the RSP and/or present in the powder in an amount within the RSP.

A particularly preferred embodiment of the powder contains a buffer salt containing at least one phosphate salt, the powder further comprising at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof, vitamin E, vitamin C, vitamin B2 and zinc and/or selenium, most preferably vitamins and minerals, administered in an amount within the RRP and/or present in the powder in an amount within the RRP.

By way of non-limiting example, a single powder dosage form may contain about 600 mg N-acetylcysteine (NAC), about 600 mg glycine, one or more phosphate salts (e.g., about 500 mg phosphate salt in total), and the RDI of each vitamin E, vitamin C, vitamin B2 and zinc.

As yet another non-limiting example, a single powder dosage form may contain about 485 mg of N-acetylcysteine (NAC), about 485 mg of glycine, one or more phosphate salts (e.g., about 500 mg of phosphate salt in total), and the RSP of each of vitamin E, vitamin C, vitamin B2, selenium and zinc.

Non-limiting examples of suitable buffer salts include citrates; phosphates such as monophosphates, diphosphates, triphosphates and polyphosphates (eg magnesium phosphate and trisodium phosphate); hexametaphosphate; carbonates such as monocarbonates and bicarbonates (eg magnesium carbonate, sodium monocarbonate, sodium bicarbonate, potassium bicarbonate and potassium monocarbonate); and mixtures thereof. The buffer salt preferably contains at least one of dibasic sodium phosphate, monobasic potassium phosphate, dipotassium phosphate, monobasic calcium phosphate, dicalcium phosphate or tricalcium phosphate; most preferably at least one of disodium phosphate or dibasic potassium phosphate. The present description is not limited to a particular embodiment of the buffer salt, and the buffer salt can be any compound that can minimize or prevent a change in pH when an acid or alkali is added to the aqueous medium in which the compound is dispersed.

The powder can be obtained by drying a liquid containing at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof, a buffer salt, and optionally at least one vitamin or mineral. Drying may include spray drying, freeze drying, or any other drying procedure known in the art. The present description is not limited to the specific embodiment of drying by which the powder is obtained, and drying can be any process that reduces moisture, for example, to form a solid composition. In an additional or alternative embodiment, the powder can be prepared by dry mixing.

In a preferred embodiment, the powder has at least one characteristic selected from the group consisting of the following: (i) the amino acid is present in an amount at least partially comprising the amino acid in a form selected from the group consisting of free form, dipeptides, tripeptides and mixtures thereof, and (ii) the powder is substantially free of enzymes and antibodies. For example, at least a portion of the amino acids may be in free form, i.e. not covalently linked to any other compound. In an additional or alternative embodiment, at least a portion of the amino acids may be present in one or more of the following forms: dipeptides; tripeptides; larger peptides (i.e., of at least four amino acid residues) or native proteins. However, in a preferred embodiment, the powder is substantially free of therapeutic proteins, such as enzymes and/or antibodies, and in a particular embodiment, completely free of therapeutic proteins, such as enzymes and/or antibodies. In some embodiments, the powder contains substantially no (or no) proteins of four or more amino acid residues. The term "substantially free" means less than 1.0% by weight, preferably less than 0.5% by weight, more preferably less than 0.2% by weight, even more preferably less than 0.1% by weight, most preferably less than 0.01 wt.%. In some embodiments, the powder is substantially composed of (or consists of) residual water (eg, after drying), a buffer salt, an amino acid, and optionally at least one vitamin or mineral.

The powder can be dissolved in a liquid such as water to form a nutritional product such as a beverage, preferably at room temperature and/or without the use of heat. In a preferred embodiment, the powder can be dissolved in a liquid containing a component selected from the group consisting of an acid component (for example, a juice and/or a polyphenol such as a flavonoid) and a protein (for example, a milk protein such as casein and/or whey ; vegetable protein; collagen; and mixtures thereof). For example, the powder can be dissolved in an oral nutritional supplement (ONS), such as the commercially available MERITENE®, BOOST®, NUTREN® and SUSTAGEN® products. However, the present description is not limited to a particular embodiment of the liquid in which the powder is dissolved, and the liquid may be any liquid suitable for animal or human consumption.

Moreover, the present description is not limited to a particular embodiment of the acidic component in the liquid, and the acidic component can be any compound that imparts acidity to the liquid. Moreover, the present disclosure is not limited to a particular embodiment of the protein in the liquid, and the protein can be any protein, especially those types that undergo denaturation or gelation when the pH is increased.

The powder may be provided to the user in a container (eg, a sealed container) to be dissolved in the container and/or to allow the user to pour the powder from the container into a drinking receptacle in which the powder is reconstituted. Non-limiting examples of suitable containers include bags, boxes, cartons, bottles, or combinations thereof. Preferred containers include a sachet/tube, i.e. a small disposable pouch, typically made of a soft film such as cellophane or paper, preferably designed to be tearable at one or both ends and containing a unit dosage form of powder (i.e., one serving of powder).

The combination of at least one glycine or a functional derivative thereof and at least one N-acetylcysteine or a functional derivative thereof can be prepared as any of the compositions described in US Pat. Nos. 8,362,080, 8,802,730 and 9,084,760, each of which is entitled Increasing glutathione levels for therapy, and US Patent Application No. 2018/0161297, entitled Benefits of Supplementation with N-Acetylcysteine and Glycine to Improve Glutathione Levels, the contents of each of which are incorporated herein by reference in their entirety.

In one embodiment, the powder unit dosage form contains a combination of at least one glycine or a functional derivative thereof and at least one N-acetylcysteine, L-cysteine or a functional derivative thereof in an amount effective to treat or prevent at least a condition selected from group consisting of the harmful effects of aging, muscle wasting (from any cause, including at least sarcopenia, HIV infection, aging, cachexia, harmful effects of weight loss), prediabetes, gestational diabetes, diabetes mellitus (type I or type II), complications of diabetes (eg, diabetic dyslipidemia and/or diabetic microvascular complications such as nephropathy, retinopathy and/or neuropathy), insulin resistance, metabolic syndrome, dyslipidemia, overweight, obesity, elevated cholesterol levels, elevated triglyceride levels, elevated fatty acids acids, fatty liver disease (eg, non-alcoholic fatty liver disease, including with or without inflammation), kidney disease, cardiovascular disease (eg, heart failure and/or abnormal contractile function of the heart, for example, by treating heart failure and/or or reducing the severity or incidence of heart failure), neurodegenerative disease (eg, as a result of aging), cognitive impairment, myopathy such as statin-induced myopathy, non-alcoholic steatohepatitis, tinnitus, dizziness, hangover, hearing impairment, osteoporosis, hypertension , atherosclerosis/coronary artery disease, myocardial damage after stress (eg, caused by burns or trauma), traumatic brain injury (including concussions), cystic fibrosis, inflammation, cancer and HIV infection. In addition, it should be noted that aging may be accompanied by a decrease in glutathione levels. Additionally, with regard to cardiovascular disease (CVD), it should be noted that increased homocysteine levels are a well-established risk factor for CVD.

Another aspect of the present invention is a liquid nutritional product comprising a buffer salt, an amino acid, and an ingredient selected from the group consisting of an acid component, a protein, and mixtures thereof, the nutritional product being prepared by a process comprising dissolving a powder containing the buffer salt and the amino acid in a liquid containing the ingredient. Preferably, the liquid nutritional product is a beverage. Dissolution can be carried out at room temperature and/or without the use of heat.

Another aspect of the present disclosure is a method of treating at least one of these conditions, comprising administering to an individual a therapeutically effective amount of a combination of at least one glycine or a functional derivative thereof and at least one N-acetylcysteine or a functional derivative thereof in a nutritional product formulated from powder containing the combination and additionally containing a buffer salt. Another aspect of the present disclosure is a method of preventing at least one of these conditions, comprising administering to an individual at risk of developing at least one condition a prophylactically effective amount of a combination of at least one glycine or a functional derivative thereof, at least one N-acetylcysteine , L-cysteine or a functional derivative thereof in a nutritional product formulated from a powder containing the combination and further containing a buffer salt.

The powder and/or resulting nutritional product may treat or prevent sarcopenia, sarcopenic obesity, or cachexia, for example, due to an underlying medical condition such as chronic disease, HIV, cancer, chronic obstructive pulmonary disease (COPD), and/or aging in otherwise healthy individuals. In this regard, aging may be accompanied by a decrease in glutathione (GSH) content.

The powder and/or resulting nutritional product may treat or prevent eye disease caused, directly or indirectly, by low levels of GSH, including low levels of GSH in the lens of the eye, which is known to be rich in glutathione. Non-limiting examples of such conditions include cataracts and/or glaucoma, presbyopia (age-related near vision loss requiring glasses) and presbycusis (age-related hearing loss requiring hearing aids).

In one embodiment, the powder and/or resulting nutritional product improves at least one of muscle performance or muscle recovery, for example, after muscle stress, including exercise-related muscle stress. The physical activity may be of any type, including, for example, aerobic (“cardiac”) exercise and/or strength training. The nutritional product may be administered at at least one of time periods selected from the group consisting of time before exercise (e.g., less than an hour), time during exercise, and time after exercise (e.g., less than an hour after physical activity).

Another aspect of the present disclosure is a method for slowing the onset of metabolic abnormalities, maintaining muscle mass, reducing oxidative stress, maintaining immune function, and/or maintaining cognitive function in a healthy older adult. The method includes administering to a healthy older adult an effective amount of a combination of at least one glycine or a functional derivative thereof and at least one N-acetylcysteine, L-cysteine or a functional derivative thereof in a nutritional product formulated from a powder containing the combination and further containing a buffered salt .

Another aspect of the present disclosure is a method of improving mitochondrial function in an individual suffering from sarcopenia. The method involves administering to an individual an effective amount of a combination of at least one glycine or a functional derivative thereof and at least one N-acetylcysteine, L-cysteine or a functional derivative thereof in a nutritional product formulated from a powder containing the combination and further comprising a buffered salt.

Another aspect of the present disclosure is a method of enhancing reactive oxygen species metabolism, improving glucose control, and/or improving muscle function in an individual with at least one of obesity, prediabetes, or diabetes. The method involves administering to an individual an effective amount of a combination of at least one glycine or a functional derivative thereof and at least one N-acetylcysteine, L-cysteine or a functional derivative thereof in a nutritional product formulated from a powder containing the combination and further comprising a buffered salt.

Another aspect of the present disclosure is a method of improving mitochondrial function (preferably to achieve a beneficial effect on at least one of metabolism or strength) in an individual suffering from sarcopenia. The method involves administering to an individual an effective amount of a combination of at least one glycine or a functional derivative thereof and at least one N-acetylcysteine, L-cysteine or a functional derivative thereof in a nutritional product formulated from a powder containing the combination and further comprising a buffered salt.

In another aspect of the present disclosure, a method for improving cognitive function is provided. The method involves administering to an individual an effective amount of a combination of at least one glycine or a functional derivative thereof and at least one N-acetylcysteine, L-cysteine or a functional derivative thereof in a nutritional product formulated from a powder containing the combination and further comprising a buffered salt. The cognitive function may be selected from the group consisting of perception, memory, attention, speech comprehension, speech generation, reading comprehension, imagery, learning, logic, and combinations thereof. In one embodiment, the individual does not have a cognitive disorder; in an alternative embodiment, the individual has a cognitive disorder. The individual may be elderly and/or may have cognitive decline associated with aging.

Another aspect of the present disclosure is a method of improving one or more of fetal metabolic programming to prevent the subsequent development of obesity, prediabetes and/or diabetes, maternal and fetal health in gestational diabetes, exercise capacity and physical function, quality of life, life expectancy, memory , cognitive function, post-traumatic recovery and survival (eg, after surgery, after sepsis, after blunt or penetrating trauma due to accidental or assault), or recovery from trauma and surgery. The method includes administering to an individual an effective amount of a combination of at least one glycine or a functional derivative thereof and at least one N-acetylcysteine or a functional derivative thereof in a nutritional product formulated from a powder containing the combination and further containing a buffered salt.

In another aspect, provided herein is a method of achieving at least one result selected from the group consisting of (i) reducing the severity and/or incidence of the effects of aging, (ii) maintaining or improving cellular function and/or general health, ( iii) maintaining at least one of normal mitochondrial function, cellular protection or energy metabolism, (iv) increasing daily energy levels, (v) reducing fatigue, (vi) maintaining or improving physical energy and/or cognitive performance, (vii) providing healthy aging by promoting healthy or normal cellular function, (viii) maintaining healthy skin, (ix) treating heart failure and/or reducing the severity or incidence of heart failure, (x) treating, reducing the incidence or severity of oxidative stress and/or reduction in glutathione (GSH) levels occurring during a period of time including an intensive care unit (ICU) stay, (xi) treatment, reduction in the incidence or severity of another condition associated with oxidative stress and/or reduced GSH (eg , aging and its consequences such as skin aging), (xii) promoting recovery from injury, illness or surgery, such as rehabilitation specific to neurological conditions such as traumatic brain injury or stroke, (xiii) modulating glutathione levels in the patient having cancer or cancer in remission, (xiv) treating, reducing the incidence or reducing the severity of symptoms of bariatric surgery, (xv) treating, reducing the incidence or reducing the severity of non-alcoholic fatty liver disease (NAFLD), (xvi) treating, reducing the incidence or reducing the severity of infection caused by the human immunodeficiency virus (HIV), and (xvii) combinations thereof, the method comprising administering to the individual an effective amount of a combination of at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof, in a nutritional product formulated from a powder containing the combination and additionally containing a buffer salt.

A particularly preferred embodiment is a method of treating, reducing the incidence of, or reducing the severity of at least one condition selected from the group consisting of metabolic syndrome, age-related metabolic decline, and muscle performance, comprising administering to a needy or at-risk individual an effective amount of a combination of at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof in a nutritional product formulated from a powder containing the combination and further containing a buffer salt.

Another aspect of the present disclosure is a method of treating, reducing the incidence, reducing the severity and/or preventing overweight and/or obesity, comprising: orally administering to an individual an effective amount of a nutritional product containing at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof, a buffer salt, and an ingredient selected from the group consisting of a protein, an acid component, and a mixture thereof, wherein the nutritional product is prepared prior to administration by a method comprising dissolving the powder in a liquid containing the ingredient, wherein the powder contains at least at least one glycine or a functional derivative thereof, at least one N-acetylcysteine. L-cysteine or their functional derivative and buffer salt.

Another aspect of the present disclosure is a method of treating, reducing the incidence, reducing the severity and/or preventing aging of the skin, comprising orally administering to an older adult or geriatric individual an effective amount of a nutritional product containing at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof, a buffer salt, and an ingredient selected from the group consisting of a protein, an acid component, and a mixture thereof, wherein the nutritional product is prepared prior to administration by a method comprising dissolving the powder in a liquid containing the ingredient, wherein the powder contains at least at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof, and a buffer salt.

Another aspect of the present disclosure is a method of promoting skin health and/or treating, reducing the incidence, reducing the severity and/or preventing a skin pathology or skin disease, comprising orally administering to a person less than 45 years of age an effective amount of a nutritional product containing at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof, a buffer salt and an ingredient selected from the group consisting of a protein, an acid component and a mixture thereof, wherein the nutritional product is prepared prior to administration by a method comprising dissolving the powder in a liquid , containing an ingredient, wherein the powder contains at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof and a buffer salt.

Another aspect of the present disclosure is a method of achieving at least one result in a healthy elderly person, wherein the at least one result is selected from the group consisting of (i) increasing levels of free reduced glutathione, (ii) increasing the ratio of free reduced glutathione to oxidized glutathione , (iii) modulating glycine and cysteine concentrations in whole blood, (iv) minimizing or preventing lipid oxidation, (v) reducing markers of oxidative damage, and (vi) shifting fuel oxidation toward fatty acids, the method comprising: orally administering to a healthy to an elderly person an effective amount of a nutritional product containing at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof, a buffer salt and an ingredient selected from the group consisting of a protein, an acid component and a mixture thereof, wherein the nutritional product is prepared prior to administration by a method comprising dissolving the powder in a liquid containing the ingredient, the powder containing at least one glycine or a functional derivative thereof, at least one N-acetylcysteine or a functional derivative thereof, and a buffer salt.

In some embodiments, the methods described herein include a dissolution step. In these embodiments, the dissolution step is preferably performed by an individual who is the recipient of the administration and/or performing the administration, and/or another individual acting under the direction of the individual who is the recipient of the administration and/or performing the administration. The liquid in which the powder is dissolved preferably contains an acidic component (for example, juice and/or a polyphenol such as a flavonoid) and/or a protein (for example, milk protein such as whey and/or casein; vegetable protein; collagen; and their mixtures).

Also provided herein is a kit containing at least one glycine or a functional derivative thereof, at least one N-acetylcysteine, L-cysteine or a functional derivative thereof, and a buffer salt in one or more containers. In some embodiments, one or more of these compounds may be isolated compounds. The kit preferably contains instructions for dissolving the mixture in a liquid containing at least one of an acidic component (for example, juice and/or a polyphenol such as a flavonoid) or a protein (for example, a milk protein such as whey and/or casein; a vegetable protein ; collagen; and mixtures thereof).

In an embodiment of the kit, at least one glycine or a functional derivative thereof, at least one N-acetylcysteine, L-cysteine or a functional derivative thereof, and a buffer salt may be provided together in one or more pre-packaged unit dosage forms, e.g. containers, each containing a dried powder such that each container contains one pre-packaged unit dosage form.

In another embodiment, the kit may contain a plurality of compositions for mixing together to form one or more of the powders described herein. For example, a kit may contain two or more dried powders in separate containers, each of the individual powders containing a portion of a finished unit dosage form.

As a non-limiting example of such an embodiment, the kit may contain one or more first containers containing at least one glycine or a functional derivative thereof, and may also contain one or more second containers containing at least one N -acetylcysteine or its functional derivative. The contents of one of the first containers may be mixed with the contents of one of the second containers to form at least a portion of a unit dosage form of the composition. In such an embodiment, the kit may have a configuration selected from the group consisting of (i) a buffer salt provided by the selected first container, (ii) a buffer salt provided by the selected second container, (iii) a portion of the buffer salt provided by the selected first container, and another portion of a buffer salt provided by the selected second container; and (iv) a buffer salt provided by at least one of a plurality of third containers.

As used herein, a "functional derivative" of glycine is a glycine derivative that is effective in combination with N-acetylcysteine or a functional derivative thereof in increasing intracellular GSH levels in an individual. A “functional derivative” of N-acetylcysteine is a derivative of N-acetylcysteine that is effective in an individual, alone or in combination with glycine (or a functional derivative thereof) to increase intracellular GSH levels.

The glycine is preferably L-glycine and/or L-glycine ethyl ester. Non-limiting examples of suitable functional glycine derivatives include D-allylglycine; N-[bis(methylthio)methylene]glycine methyl ester; Boc-allyl-Gly-OH (dicyclohexylammonium) salt; Boc-D-Chg-OH; Boc-Chg-OH; (R)-N-Boc-(2'-chlorophenyl)glycine; Boc-L-cyclopropylglycine; Boc-L-cyclopropylglycine; (R)-N-Boc-4-fluorophenylglycine; Boc-D-propargylglycine; Boc-(S)-3-thienylglycine; Boc-(R)-3-thienylglycine; D-a-cyclohexylglycine; L-a-cyclopropylglycine; N-(2-fluorophenyl)-N-(methylsulfonyl)glycine; N-(4-fluorophenyl)-N-(methylsulfonyl)glycine; Fmoc-N-(2,4-dimethoxybenzyl)-Gly-OH; N-(2-furoyl)glycine; L-a-neopentylglycine; D-propargylglycine; sarcosine; Z-a-phosphonoglycine trimethyl ester and mixtures thereof.

The powder and/or resulting nutritional product may be administered at least one day per week, preferably at least two days per week, more preferably at least three or four days per week (e.g., every other day), most preferably at least five days a week, six days a week or seven days a week. The administration period may be at least one week, preferably at least one month, more preferably at least two months, most preferably at least three months, for example at least four months. In one embodiment, administration is performed at least daily; for example, the subject may receive one or more doses daily. In some embodiments, administration continues for the remainder of the individual's life. In other embodiments, administration occurs until no noticeable symptoms of the medical condition remain. In certain embodiments, administration occurs until there is detectable improvement in at least one symptom, and in other cases while relief is maintained.

Glycine and N-acetylcysteine or L-cysteine or a functional derivative thereof can be prepared in a certain ratio. In some embodiments, the formulation may contain these components in the following approximate ratios: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1: 65, 1: 70, 1: 75, 1: 80, 1: 85, 1: 90, 1: 95, 1: 100, 1: 150, 1: 200, 1: 300, 1: 400, 1: 500, 1:600, 1:750, 1:1000, and 1:10,000, and each of these ratios in some embodiments may be a GLY:NAC ratio and in other embodiments may be a NAC:GLY ratio. In specific embodiments, the formulation may contain these components in the following weight percentages (either the same for both glycine and N-acetylcysteine, or different weight percentages for each): for example, 1%, 2%, 3% , 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60 %, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99%.

N-acetylcysteine or a functional derivative thereof may be administered in an amount of about 0.1 to 100 milligrams (mg) of N-acetylcysteine (NAC) or a functional derivative thereof per kilogram (kg) of the subject's body weight. Glycine (GLY) or a functional derivative thereof can be administered in an amount of about 0.1 to 100 milligrams (mg) of glycine or a functional derivative thereof per kilogram (kg) of the subject's body weight. In some embodiments, these amounts are provided at least in part by a dipeptide containing both N-acetylcysteine or a functional derivative thereof and glycine or a functional derivative thereof.

In a specific non-limiting example, daily dosages for a subject weighing 60 kg may be as follows:

NAC or its functional derivative: 6 to 6000 mg/day;

GLY or its functional derivative: 6 to 6000 mg/day.

The ratio of buffer salts to amino acids may depend on the specific application of the resulting product (eg, whether the reconstituted liquid is a beverage or some other type of composition), the portion size of the resulting product, and the protein content of the resulting product. However, one skilled in the art will be able to use the disclosures provided herein to determine the appropriate ratio of buffer salts to amino acids based on these factors.

The powder and/or resulting nutritional product described herein is preferably administered orally to a subject. Thus, non-limiting examples of composition forms include natural foods, processed foods, natural juices, concentrates and extracts, liposomes and sustained release formulations.

The powder and/or resulting nutritional product described herein can be used in any of various formulations for therapeutic administration. More specifically, pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers or diluents and may be formulated in solid, semi-solid, liquid or gaseous forms. Thus, administration of the composition can be achieved in various ways, but preferably orally.

In pharmaceutical dosage forms, the compounds can be administered as their pharmaceutically acceptable salts. They may also be used in suitable association with other pharmaceutically active compounds. The following methods and excipients are provided by way of example only and are not intended to be limiting in any way.

In the case of oral preparations, the compounds can be used alone or in combination with appropriate additives to obtain tablets, powders, granules, for example with conventional additives such as lactose, mannitol, maltodextrin, corn starch or potato starch; with binders such as crystalline cellulose, functional cellulose derivatives, gum arabic, corn starch or gelatins; with disintegrants such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants such as talc or magnesium stearate; and, if necessary, with diluents, buffering agents, wetting agents, preservatives and flavoring agents.

Example

The following non-limiting example provided by the present inventors further supports the compounds, compositions and methods described herein.

Prerequisites

Standard protein or amino acid powder form does not contain buffer salts, with the exception of “therapeutic/active” proteins such as enzymes or antibodies. For example, such specific compounds are unstable in their pure form and therefore require additional salts for stabilization. In contrast, amino acids are provided without buffer salts.

Buffering salts are also common in many applications in ready-to-drink protein products, with the additional use of alkaline solutions such as potassium hydroxide or sodium hydroxide since ready-to-drink beverages are typically heat-treated. However, powdered products that are designed to be dissolved in liquids at room temperature or in cold liquids immediately prior to consumption are provided without buffering salts.

Thus, the present inventors have explored a solution for dissolving amino acids such as glycine and/or NAC in a liquid that is acidic and/or containing protein, such as dissolving amino acid powder at home.

Experiments

The inventors of the present invention dissolved various amino acid powders at room temperature without heat treatment. The amino acids, mixed with or without buffer salts, were then poured into the drink.

Specifically, 600 mg of N-acetylcysteine (NAC) and 600 mg of glycine were added to 100 ml of water and stirred. 27.5 g of unflavored milk protein powder was then added and mixed. Another sample mixed 200 mg of disodium phosphate and 300 mg of dibasic potassium phosphate with 600 mg of NAC and 600 mg of glycine. The mixture was then added to 100 ml of water and stirred. After this, 27.5 grams of unflavored powder containing milk protein was added and mixed. The use of disodium phosphate and dibasic potassium phosphate significantly reduced protein denaturation and precipitation.

In this regard, in the photographs of FIG. 1–4 show the bottom of the cup. In fig. 1 shows the result of dissolving powdered NAC without buffer salts; FIG. 2 shows the result of dissolving powdered NAC with buffer salts; FIG. 3 shows the result of dissolving powdered NAC and glycine without buffer salts, and FIG. Figure 4 shows the result of dissolving powdered NAC and glycine with buffer salts. As shown in the figures, in the absence of buffer salts, residues are present, and the presence of buffer salts avoids precipitation.

It should be understood that various changes and modifications to the currently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. Accordingly, the appended claims are intended to cover such changes and modifications.

Claims (24)

1. Powder for obtaining a nutritional product containing a phosphate salt, at least one glycine or a functional derivative thereof, at least one N-acetylcysteine, L-cysteine or a functional derivative thereof, vitamin E, vitamin C, vitamin B ₂ and zinc, wherein the powder has at least one characteristic selected from the group consisting of the following: (i) the amino acids are present in the powder in an amount at least partially comprising the amino acid in a form selected from the group consisting of free form, dipeptides, tripeptides, and mixtures, and (ii) the powder is substantially free of enzymes and antibodies. 2. The powder of claim 1, which is in unit dosage form containing each of vitamin E, vitamin C, vitamin B ₂ and zinc in an amount within the recommended daily allowance. 3. The powder according to claim 1 or 2, in which the phosphate salt is monophosphate, diphosphate, triphosphate and polyphosphate; hexametaphosphate; or mixtures thereof. 4. Powder according to any one of paragraphs. 1-3, wherein the phosphate salt is selected from the group consisting of dibasic sodium phosphate, monobasic potassium phosphate, dipotassium phosphate, monobasic calcium phosphate, dicalcium phosphate, tricalcium phosphate, disodium phosphate, dibasic potassium phosphate and mixtures thereof. 5. Powder according to any one of paragraphs. 1-4, additionally containing citrates; carbonates such as monocarbonates and bicarbonates; or mixtures thereof. 6. Powder according to any one of paragraphs. 1-5, additionally containing magnesium carbonate, sodium monocarbonate, sodium bicarbonate, potassium bicarbonate, potassium monocarbonate or mixtures thereof. 7. Powder according to any one of paragraphs. 1-6, which further contains an acidic amino acid. 8. Powder according to any one of paragraphs. 1-7, further containing at least one vitamin or mineral. 9. Powder according to any one of paragraphs. 1-8, further containing at least one of calcium, sodium or potassium. 10. Powder according to any one of paragraphs. 1-9, which contains L-cysteine, glycine and additionally L-glutamate, which are represented in powder by glutathione. 11. Powder according to any one of paragraphs. 1-10, which additionally contains selenium. 12. Powder according to any one of paragraphs. 1-11, which is in a unit dosage form containing a combination of at least one N-acetylcysteine, L-cysteine or a functional derivative thereof and at least one glycine or a functional derivative thereof in an amount effective to treat, reduce the incidence or reduce the severity of at least one condition selected from the group consisting of metabolic syndrome, age-related metabolic decline, and muscle performance. 13. Powder according to any one of paragraphs. 1-12, which is in a unit dosage form containing a combination of at least one N-acetylcysteine, L-cysteine or a functional derivative thereof and at least one glycine or a functional derivative thereof in an amount effective for at least one of (i ) treating or preventing at least one physical condition selected from the group consisting of oxidative stress, a condition associated with oxidative stress, reduced glutathione levels, a condition associated with reduced glutathione levels, or (ii) improving one or more of metabolic programming fetus to prevent subsequent development of obesity, prediabetes and/or diabetes, maternal and fetal health in gestational diabetes, exercise capacity and physical function, quality of life, life expectancy, memory, cognitive function, post-traumatic recovery and survival or recovery from injury and surgery . 14. Powder according to any one of paragraphs. 1-13, which is in a unit dosage form containing a combination of at least one N-acetylcysteine, L-cysteine or a functional derivative thereof and at least one glycine or a functional derivative thereof in an amount effective to treat or prevent at least one physical condition selected from the group consisting of the harmful effects of aging, muscle wasting, prediabetes, gestational diabetes, type I diabetes, type II diabetes, complications of diabetes, insulin resistance, metabolic syndrome, dyslipidemia, overweight, obesity, elevated cholesterol levels, elevated triglyceride levels, elevated fatty acid levels, fatty liver, kidney disease, cardiovascular disease, neurodegenerative disease, cognitive impairment, myopathy such as statin-induced myopathy, nonalcoholic steatohepatitis, tinnitus, dizziness, hangover syndrome, hearing impairment , osteoporosis, hypertension, atherosclerosis/coronary artery disease, myocardial injury after stress, traumatic brain injury, cystic fibrosis, inflammation, cancer and HIV infection. 15. Powder according to any one of paragraphs. 1-14, which is substantially free of proteins having at least four amino acid residues. 16. A method of reducing or preventing protein denaturation and protein coagulation caused by dissolving a powder in a liquid containing an ingredient selected from the group consisting of a protein or a mixture of a protein and an acid component, the method including a step selected from the group consisting of (i ) dry mixing the phosphate salt with the amino acid and (ii) drying an aqueous solution containing the phosphate salt and the amino acid, wherein the powder contains the phosphate salt, at least one glycine or a functional derivative thereof, at least one N-acetylcysteine, L-cysteine or the same functional derivative, vitamin E, vitamin C, vitamin B ₂ and zinc, wherein the powder has at least one characteristic selected from the group consisting of the following: (i) amino acids are present in the powder in an amount at least partially comprising the amino acid in form selected from the group consisting of free form, dipeptides, tripeptides and mixtures thereof, and (ii) the powder is substantially free of enzymes and antibodies. 17. The method of claim 16, wherein the powder further contains at least one vitamin or mineral. 18. The method according to claim 16 or 17, in which the powder additionally contains selenium. 19. A liquid nutritional product containing a phosphate salt, at least one glycine or a functional derivative thereof, at least one N-acetylcysteine, L-cysteine or a functional derivative thereof, vitamin E, vitamin C, vitamin _B2 , zinc and an ingredient, selected from the group consisting of an acid component, a protein, and mixtures thereof, wherein the nutritional product is prepared by a process comprising dissolving a powder containing a phosphate salt, at least one glycine, or a functional derivative thereof, at least one N-acetylcysteine, L- cysteine or a functional derivative thereof, vitamin E, vitamin C, vitamin B ₂ and zinc, in a liquid containing the ingredient, wherein the powder has at least one characteristic selected from the group consisting of the following: (i) amino acids are present in the powder in an amount , at least partially comprising an amino acid in a form selected from the group consisting of free form, dipeptides, tripeptides and mixtures thereof, and (ii) the powder is substantially free of enzymes and antibodies. 20. The nutritional product of claim 19, wherein the powder is dissolved from a unit dosage form containing each of vitamin E, vitamin C, vitamin B ₂ and zinc in an amount within the recommended daily allowance. 21. Nutritional product according to claim 19 or 20, which additionally contains selenium. 22. Nutritional product according to any one of paragraphs. 19-21, which is a drink. 23. Nutritional product according to any one of paragraphs. 19-22, wherein the liquid contains an acidic component, which is at least one of a juice or a polyphenol. 24. Nutritional product according to any one of paragraphs. 19-23, wherein the liquid contains a protein selected from the group consisting of milk protein, vegetable protein, collagen and mixtures thereof.